CN107868065A - A kind of Flubuperone Hydrochloride compound and preparation method thereof - Google Patents
A kind of Flubuperone Hydrochloride compound and preparation method thereof Download PDFInfo
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- CN107868065A CN107868065A CN201710977729.8A CN201710977729A CN107868065A CN 107868065 A CN107868065 A CN 107868065A CN 201710977729 A CN201710977729 A CN 201710977729A CN 107868065 A CN107868065 A CN 107868065A
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- hexahydropyridine
- acetone
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- hydrochloride
- flubuperone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
- C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/108—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a kind of Flubuperone Hydrochloride compound and preparation method thereof, described Flubuperone Hydrochloride compound is crystal.Flubuperone Hydrochloride compound purity prepared by the present invention is high, stability is good, and the preparation method of Flubuperone Hydrochloride is simple, and product quality is stable, and environmental pollution is small, suitable further genralrlization application.
Description
Technical field
The invention belongs to pharmaceutical technology field, is related to a kind of Flubuperone Hydrochloride compound and preparation method thereof.
Background technology
Flubuperone Hydrochloride is also known as Tolperisone, chemical name：2- methyl isophthalic acids-（4- aminomethyl phenyls）-3-（1- piperidyls）- 1- third
Keto hydrochloride, central muscle relaxant, there is expansion blood vessel function.For treating ischemic vascular disease, such as artery sclerosis, blood vessel
Intimitis etc.；It is additionally operable to apoplexy sequelae, cerebral paralysis disease, spinal cord nerve ending illness etc..Various cranial vascular diseases are caused
Headache, the symptom such as dizziness, insomnia, limbs are numb, failure of memory, tinnitus have certain curative effect.
Cranial vascular disease is a kind of global common disease, by Flubuperone Hydrochloride as main component vasodilator agent at me
There is extensive Clinical practice in state patient groups, curative effect is prominent and cheap.
Because the positive therapeutic of Flubuperone Hydrochloride, a kind of more stable Flubuperone Hydrochloride compound of research is for hydrochloric acid support
The application of piperazine ketone has positive role.The present inventor unexpectedly obtains one during for a long time to the numerous studies of Flubuperone Hydrochloride
Flubuperone Hydrochloride compound of kind crystal form and preparation method thereof, the Flubuperone Hydrochloride compound prepared by this method has
High quality stability, add the security of medication, hence it is evident that better than prior art
The content of the invention
The present invention provides a kind of Flubuperone Hydrochloride compound of stabilization.
Flubuperone Hydrochloride structural formula of compound such as formula provided by the invention（Ⅰ）It is shown：
Formula（Ⅰ）
Described Flubuperone Hydrochloride compound is crystal, is determined using X- ray powder diffractions, in its collection of illustrative plates characteristic peak 2 θ ±
0.2 ° is 7.0 °, 17.1 °, 17.9 °, 19.3 °, 20.3 °, 22.1 °, 25.6 °, 25.9 ° and shows.
The X-ray powder diffraction figure of described Flubuperone Hydrochloride compound is shown in Fig. 1.
Flubuperone Hydrochloride compounds process for production thereof of the present invention comprises the following steps：
（1）It is condensed into salt
Ethanol, hexahydropyridine are put into reactor, opens chilled water cooling, it is 24~28 DEG C to control temperature, 60~70
Ethanol solution hydrochloride is added dropwise under rev/min mixing speed（w%:30.0~35.0%）, continue stirring reaction after completion of dropwise addition 20 minutes；
Wherein ethanol, hexahydropyridine, ethanol solution hydrochloride dosage weight ratio（W/W）For：Hexahydropyridine：Ethanol：Ethanol solution hydrochloride=1:
0.65：1.2~1.4；
Formalin is added in reactor（w%≥36.5%）, P-Methyl phenylethylketone, heating reflux reaction 16 hours；Wherein
Formalin, P-Methyl phenylethylketone and stepIn hexahydropyridine dosage weight ratio（W/W）For：Hexahydropyridine：Formalin：
P-Methyl phenylethylketone=1:2.4:1.8；
Reaction finishes, air-distillation, terminates when steaming to 105 DEG C of Nei Wenda, and it is 30~40 DEG C to be cooled to temperature in reactor, is added
Enter purified water, stir 30~40 minutes, obtain reaction solution；Wherein purified water and stepIn hexahydropyridine dosage weight ratio（W/
W）For：Hexahydropyridine：Purified water=1:7；
In and washing kettle adds purified water, and temperature control is 30~40 DEG C, and stirring adds sodium carbonate dissolving, by step
Obtained reaction solution, which is evacuated to, to be neutralized in washing kettle, is stirred 20~30 minutes, static layering 20 minutes, is discarded lower floor's aqueous alkali,
Retain upper strata oily liquid；Wherein purified water, sodium carbonate and stepIn hexahydropyridine dosage weight ratio（W/W）For：Hexahydro pyrrole
Pyridine：Purified water：Sodium carbonate=1:7:1.7；
With the saturated aqueous common salt prepared at room temperature washing step in three timesObtained oily liquid, stir 20 minutes every time,
Stand 15 minutes, discard lower floor's washings, obtain 2- methyl isophthalic acids-（4- aminomethyl phenyls）-3-（1- piperidyls）- 1- acetone；It is embezzled
With the dosage and step of saline solution（1）In hexahydropyridine dosage weight ratio（W/W）For：Hexahydropyridine：Saturated aqueous common salt=1:
14；
（2）It is refined
In enamel reaction still put into acetone, 2- methyl isophthalic acids-（4- aminomethyl phenyls）-3-（1- piperidyls）- 1- acetone, 60~
Ethanol solution hydrochloride is added dropwise under 70 revs/min of mixing speeds（w%:30.0~35.0%）, it is 32~35 DEG C to control temperature, is added dropwise to pH
It is worth for 3.0~3.2；Wherein acetone, 2- methyl isophthalic acids-（4- aminomethyl phenyls）-3-（1- piperidyls）- 1- acetone dosage weight ratios（W/
W）For：Acetone：2- methyl isophthalic acids-（4- aminomethyl phenyls）-3-（1- piperidyls）- 1- acetone=3:1；
Toward stepIn solution in add activated carbon, be warming up to backflow decolourize 30 minutes, filter while hot, filtrate enter crystallization
Kettle, it is cooled to 6~8 DEG C of insulations and crystallizes 1 hour；The wherein dosage and step of activated carbonMiddle 2- methyl isophthalic acids-（4- methylbenzenes
Base）-3-（1- piperidyls）- 1- acetone dosage weight ratios（W/W）For：2- methyl isophthalic acids-（4- aminomethyl phenyls）-3-（1- piperidyls）-
1- acetone：Activated carbon=70:1；
By stepObtained material is put to centrifuge, dries to obtain finished product wet feed, and by wet feed sabot, sabot thickness is not
More than 2 centimetres, it is placed in dry case, is crushed after 98~102 DEG C of forced air drying 6-8 hours, cross 40 mesh sieves, produces described hydrochloric acid
Tolperisone compound.
It is reaction temperature, the time, speed of agitator, anti-it should be noted that a kind of formation of crystal formation is influenced by many factors
Unexpected change may be produced by answering any one factor such as thing concentration, crystallization condition control that even if the change of very little occurs
Change, such as：It is condensed into salt：Ethanol consumption, mixing speed in step 1；Chilling temperature in step 3,4；It is refined：Step 6 stirs
Speed, temperature control, pH value control, step 7 temperature control etc. exceed amount ranges of the present invention, even if very small change
Flubuperone Hydrochloride compound of the present invention can not be all obtained, the present inventor undergoes many failures in research process, but most
Great effort is taken eventually to study control details, obtains Flubuperone Hydrochloride compound of the present invention, this hair of the above finally
Each control parameter main points in bright described preparation of compounds are most important to result.
Brief description of the drawings：
Fig. 1 is the X-ray powder diffraction figure of Flubuperone Hydrochloride compound prepared by the embodiment of the present invention 1.
Embodiment：
The preparation of the Flubuperone Hydrochloride compound of embodiment 1
Comprise the following steps（1-5 is to be condensed process into salt, and 6-8 is refining step）：
1st, 19.5Kg ethanol and 30Kg hexahydropyridine are put into reactor, opens chilled water cooling, it is 24 DEG C to control temperature,
36Kg ethanol solution hydrochloride is added dropwise under 60 revs/min of mixing speeds（w%:30.0%）, continue stirring reaction 20 after completion of dropwise addition
Minute；
2nd, 72Kg formalin is added in reactor（w%：36.5%）With 54Kg P-Methyl phenylethylketone, heating reflux reaction
16 hours；
3rd, reaction finishes, air-distillation, terminates when steaming to 105 DEG C of Nei Wenda, and it is 30 DEG C to be cooled to temperature in reactor, is added
210Kg purified water, stir 30 minutes, obtain reaction solution；
4th, in and washing kettle add 210Kg purified water, temperature control be 30 DEG C, stirring add 51Kg sodium carbonate dissolving,
The reaction solution that step 3 is obtained, which is evacuated to, to be neutralized in washing kettle, is stirred 20 minutes, static layering 20 minutes, it is molten to be discarded lower floor's buck
Liquid, retain upper strata oily liquid；
5th, with the 420Kg prepared at room temperature the saturated aqueous common salt oily liquid that washing step 4 obtains in three times, 20 are stirred every time
Minute, stand 15 minutes, discard lower floor's washings, obtain 2- methyl isophthalic acids-（4- aminomethyl phenyls）-3-（1- piperidyls）- 1- acetone；；
6th, put into enamel reaction still 210Kg acetone, 70Kg 2- methyl isophthalic acids-（4- aminomethyl phenyls）-3-（1- piperidyls）-
1- acetone, ethanol solution hydrochloride is added dropwise under 60 revs/min of mixing speeds（w%:30.0）, it is 32 DEG C to control temperature, is added dropwise to pH value
For 3.0；
7th, toward the activated carbon of addition 1Kg in the solution in step 6, it is warming up to backflow and decolourizes 30 minutes, filter while hot, filtrate enters knot
Brilliant kettle, it is cooled to 6 DEG C of insulations and crystallizes 1 hour；
8th, the material for obtaining step 7 is put to centrifuge, dries to obtain finished product wet feed, by wet feed sabot, 1 li of sabot thickness
Rice, is placed in dry case, is crushed in 98 DEG C of forced air dryings after 8 hours, crosses 40 mesh sieves, produce described Flubuperone Hydrochloride compound.
X-ray powder diffraction figure is shown in accompanying drawing 1, in its collection of illustrative plates characteristic peak 2 θ be 7.0 °, 17.1 °, 17.9 °, 19.3 °, 20.3 °,
22.1 °, 25.6 °, 25.9 ° of displays.Content：99.97%.
The preparation of the Flubuperone Hydrochloride compound of embodiment 2
Comprise the following steps（1-5 is to be condensed process into salt, and 6-8 is refining step）：
1st, 19.5Kg ethanol and 30Kg hexahydropyridine are put into reactor, opens chilled water cooling, it is 28 DEG C to control temperature,
42Kg ethanol solution hydrochloride is added dropwise under 70 revs/min of mixing speeds（w%:35.0%）, continue stirring reaction 20 after completion of dropwise addition
Minute；
2nd, 72Kg formalin is added in reactor（w%：37.0%）With 54Kg P-Methyl phenylethylketone, heating reflux reaction
16 hours；
3rd, reaction finishes, air-distillation, terminates when steaming to 105 DEG C of Nei Wenda, and it is 40 DEG C to be cooled to temperature in reactor, is added
210Kg purified water, stir 40 minutes, obtain reaction solution；
4th, in and washing kettle add 210Kg purified water, temperature control be 40 DEG C, stirring add 51Kg sodium carbonate dissolving,
The reaction solution that step 3 is obtained, which is evacuated to, to be neutralized in washing kettle, is stirred 20 minutes, static layering 20 minutes, it is molten to be discarded lower floor's buck
Liquid, retain upper strata oily liquid；
5th, with the 420Kg prepared at room temperature the saturated aqueous common salt oily liquid that washing step 4 obtains in three times, 20 are stirred every time
Minute, stand 15 minutes, discard lower floor's washings, obtain 2- methyl isophthalic acids-（4- aminomethyl phenyls）-3-（1- piperidyls）- 1- acetone；；
6th, put into enamel reaction still 210Kg acetone, 70Kg 2- methyl isophthalic acids-（4- aminomethyl phenyls）-3-（1- piperidyls）-
1- acetone, ethanol solution hydrochloride is added dropwise under 70 revs/min of mixing speeds（w%:35.0%）, it is 35 DEG C to control temperature, is added dropwise to pH value
For 3.2；
7th, toward the activated carbon of addition 1Kg in the solution in step 6, it is warming up to backflow and decolourizes 30 minutes, filter while hot, filtrate enters knot
Brilliant kettle, it is cooled to 8 DEG C of insulations and crystallizes 1 hour；
8th, the material for obtaining step 7 is put to centrifuge, dries to obtain finished product wet feed, by wet feed sabot, 2 lis of sabot thickness
Rice, is placed in dry case, is crushed in 102 DEG C of forced air dryings after 6 hours, crosses 40 mesh sieves, produce described Flubuperone Hydrochloride compound.
X-ray powder diffraction figure is consistent with embodiment 1.Content：99.93%.
The preparation of the Flubuperone Hydrochloride compound of embodiment 3
Comprise the following steps（1-5 is to be condensed process into salt, and 6-8 is refining step）：
1st, 19.5Kg ethanol and 30Kg hexahydropyridine are put into reactor, opens chilled water cooling, it is 26 DEG C to control temperature,
38Kg ethanol solution hydrochloride is added dropwise under 65 revs/min of mixing speeds（w%:33.0%）, continue stirring reaction 20 after completion of dropwise addition
Minute；
2nd, 72Kg formalin is added in reactor（w%：37.0%）With 54Kg P-Methyl phenylethylketone, heating reflux reaction
16 hours；
3rd, reaction finishes, air-distillation, terminates when steaming to 105 DEG C of Nei Wenda, and it is 35 DEG C to be cooled to temperature in reactor, is added
210Kg purified water, stir 35 minutes, obtain reaction solution；
4th, in and washing kettle add 210Kg purified water, temperature control be 35 DEG C, stirring add 51Kg sodium carbonate dissolving,
The reaction solution that step 3 is obtained, which is evacuated to, to be neutralized in washing kettle, is stirred 25 minutes, static layering 20 minutes, it is molten to be discarded lower floor's buck
Liquid, retain upper strata oily liquid；
5th, with the 420Kg prepared at room temperature the saturated aqueous common salt oily liquid that washing step 4 obtains in three times, 20 are stirred every time
Minute, stand 15 minutes, discard lower floor's washings, obtain 2- methyl isophthalic acids-（4- aminomethyl phenyls）-3-（1- piperidyls）- 1- acetone；；
6th, put into enamel reaction still 210Kg acetone, 70Kg 2- methyl isophthalic acids-（4- aminomethyl phenyls）-3-（1- piperidyls）-
1- acetone, ethanol solution hydrochloride is added dropwise under 65 revs/min of mixing speeds（w%:33.0%）, it is 33 DEG C to control temperature, is added dropwise to pH value
For 3.1；
7th, toward the activated carbon of addition 1Kg in the solution in step 6, it is warming up to backflow and decolourizes 30 minutes, filter while hot, filtrate enters knot
Brilliant kettle, it is cooled to 7 DEG C of insulations and crystallizes 1 hour；
8th, the material for obtaining step 7 is put to centrifuge, dries to obtain finished product wet feed, by wet feed sabot, 1.5 lis of sabot thickness
Rice, is placed in dry case, is crushed in 100 DEG C of forced air dryings after 7 hours, crosses 40 mesh sieves, produce described Flubuperone Hydrochloride compound.
X-ray powder diffraction figure is consistent with embodiment 1.Content：99.92%.
The present invention provides tests below and comparing result：
Sample 1：Flubuperone Hydrochloride compound prepared by the embodiment of the present invention 1
Sample 2：Commercially available Flubuperone Hydrochloride
Sample 1~2 is subjected to accelerated stability investigation（40 DEG C ± 2 DEG C, RH 75% ± 5%）, the results are shown in Table 1.
The Flubuperone Hydrochloride accelerated test result of table 1
The Flubuperone Hydrochloride compound stability that it can be seen from the result of table 1 prepared by the present invention is good, with prior art compared to tool
There is obvious advantage.Flubuperone Hydrochloride compound prepared by other embodiments of the invention has also carried out identical experiment, obtains
Similar result.
Claims (2)
1. Flubuperone Hydrochloride compound, structural formula is as shown in formula I：
Formula I
It is characterized in that：Described Flubuperone Hydrochloride compound is crystal, is determined using X- ray powder diffractions, in its collection of illustrative plates
Characteristic peak is 7.0 °, 17.1 °, 17.9 °, 19.3 °, 20.3 °, 22.1 °, 25.6 °, 25.9 ° in 2 θ ± 0.2 ° and shown.
2. the preparation method of the Flubuperone Hydrochloride compound described in claim 1, comprises the following steps：
（1）It is condensed into salt
Ethanol, hexahydropyridine are put into reactor, chilled water cooling is opened, control temperature as 24~28 DEG C, 60~70 turns/
Ethanol solution hydrochloride is added dropwise under point mixing speed（w%:30.0~35.0%）, continue stirring reaction after completion of dropwise addition 20 minutes；Its
Middle ethanol, hexahydropyridine, ethanol solution hydrochloride dosage weight ratio（W/W）For：Hexahydropyridine：Ethanol：Ethanol solution hydrochloride=1:
0.65：1.2~1.4；
Formalin is added in reactor（w%≥36.5%）, P-Methyl phenylethylketone, heating reflux reaction 16 hours；Wherein
Formalin, P-Methyl phenylethylketone and stepIn hexahydropyridine dosage weight ratio（W/W）For：Hexahydropyridine：Formaldehyde is molten
Liquid：P-Methyl phenylethylketone=1:2.4:1.8；
Reaction finishes, air-distillation, terminates when steaming to 105 DEG C of Nei Wenda, and it is 30~40 DEG C to be cooled to temperature in reactor, is added
Purified water, stir 30~40 minutes, obtain reaction solution；Wherein purified water and stepIn hexahydropyridine dosage weight ratio（W/W）
For：Hexahydropyridine：Purified water=1:7；
In and washing kettle adds purified water, and temperature control is 30~40 DEG C, and stirring adds sodium carbonate dissolving, by step
To reaction solution be evacuated to neutralize washing kettle in, stir 20~30 minutes, static layering 20 minutes, discard lower floor's aqueous alkali, protect
Stay upper strata oily liquid；Wherein purified water, sodium carbonate and stepIn hexahydropyridine dosage weight ratio（W/W）For：Hexahydropyridine：
Purified water：Sodium carbonate=1:7:1.7；
With the saturated aqueous common salt prepared at room temperature washing step in three timesObtained oily liquid, stir 20 minutes every time,
Stand 15 minutes, discard lower floor's washings, obtain 2- methyl isophthalic acids-（4- aminomethyl phenyls）-3-（1- piperidyls）- 1- acetone；It is embezzled
With the dosage and step of saline solution（1）In hexahydropyridine dosage weight ratio（W/W）For：Hexahydropyridine：Saturated aqueous common salt=1:
14；
（2）It is refined
In enamel reaction still put into acetone, 2- methyl isophthalic acids-（4- aminomethyl phenyls）-3-（1- piperidyls）- 1- acetone, 60~
Ethanol solution hydrochloride is added dropwise under 70 revs/min of mixing speeds（w%:30.0~35.0%）, it is 32~35 DEG C to control temperature, is added dropwise to pH
It is worth for 3.0~3.2；Wherein acetone, 2- methyl isophthalic acids-（4- aminomethyl phenyls）-3-（1- piperidyls）- 1- acetone dosage weight ratios（W/
W）For：Acetone：2- methyl isophthalic acids-（4- aminomethyl phenyls）-3-（1- piperidyls）- 1- acetone=3:1；
Toward stepIn solution in add activated carbon, be warming up to backflow decolourize 30 minutes, filter while hot, filtrate enter crystallization
Kettle, it is cooled to 6~8 DEG C of insulations and crystallizes 1 hour；The wherein dosage and step of activated carbonMiddle 2- methyl isophthalic acids-（4- aminomethyl phenyls）-
3-（1- piperidyls）- 1- acetone dosage weight ratios（W/W）For：2- methyl isophthalic acids-（4- aminomethyl phenyls）-3-（1- piperidyls）- 1- third
Ketone：Activated carbon=70:1；
By stepObtained material is put to centrifuge, dries to obtain finished product wet feed, and by wet feed sabot, sabot thickness is not
More than 2 centimetres, it is placed in dry case, is crushed after 98~102 DEG C of forced air drying 6-8 hours, cross 40 mesh sieves, produces described hydrochloric acid
Tolperisone compound.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110845443A (en) * | 2019-12-11 | 2020-02-28 | 嘉实（湖南）医药科技有限公司 | Method for preparing high-purity tolperisone hydrochloride |
| CN113101319A (en) * | 2021-04-16 | 2021-07-13 | 一力制药股份有限公司 | Tolperisone hydrochloride composition and application thereof |
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| JPS5295674A (en) * | 1976-02-09 | 1977-08-11 | Nippon Carbide Ind Co Ltd | Preparation of 4#-substituted-2-methyl-2-piperidinopropiophenone and i ts salts |
| JPS57159045A (en) * | 1981-03-27 | 1982-10-01 | Hitachi Ltd | Manufacture of multilayer wiring structure |
| US20060041141A1 (en) * | 2002-12-05 | 2006-02-23 | Laszlo Czollner | Method for producing salts of tolperisone |
| CN101754958A (en) * | 2007-04-26 | 2010-06-23 | 萨诺化学药物股份公司 | Prepare highly purified 2,4 '-method of dimethyl-3-piperidines-Propiophenone (tolperisone), the active substance formulations that comprises its pharmaceutical composition and comprise tolperisone |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPS4020390Y1 (en) * | 1964-07-16 | 1965-07-15 | ||
| JPS5295674A (en) * | 1976-02-09 | 1977-08-11 | Nippon Carbide Ind Co Ltd | Preparation of 4#-substituted-2-methyl-2-piperidinopropiophenone and i ts salts |
| JPS57159045A (en) * | 1981-03-27 | 1982-10-01 | Hitachi Ltd | Manufacture of multilayer wiring structure |
| US20060041141A1 (en) * | 2002-12-05 | 2006-02-23 | Laszlo Czollner | Method for producing salts of tolperisone |
| CN101754958A (en) * | 2007-04-26 | 2010-06-23 | 萨诺化学药物股份公司 | Prepare highly purified 2,4 '-method of dimethyl-3-piperidines-Propiophenone (tolperisone), the active substance formulations that comprises its pharmaceutical composition and comprise tolperisone |
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| Title |
|---|
| KAZUHARU SUMITA等: "A modified Mannich reaction using 1,3-dioxolane", 《CHEM. PHARM. BULL.》 * |
| RUMIKO TANAKA等: "Structure of Tolperisone Monohydrochloride", 《ANALYTICAL SCIENCES: X-RAY STRUCTURE ANALYSIS ONLINE》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110845443A (en) * | 2019-12-11 | 2020-02-28 | 嘉实（湖南）医药科技有限公司 | Method for preparing high-purity tolperisone hydrochloride |
| CN110845443B (en) * | 2019-12-11 | 2023-09-05 | 嘉实（湖南）医药科技有限公司 | Method for preparing high-purity tolperisone hydrochloride |
| CN113101319A (en) * | 2021-04-16 | 2021-07-13 | 一力制药股份有限公司 | Tolperisone hydrochloride composition and application thereof |
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| CN107868065B (en) | 2021-05-18 |
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